Results from Pioneer: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent Systemic Mastocytosis

Introduction: Patients with non-advanced systemic mastocytosis (SM), such as indolent systemic mastocytosis (ISM), often develop chronic and debilitating symptoms caused by mast cell (MC) proliferation/hyperactivation primarily driven by KIT D816V mutation. There are no approved disease-modifying therapies for patients with ISM. Avapritinib, a potent oral KIT D816V inhibitor, markedly reduced MC burden in a phase 1 study in patients with advanced SM.

Methods: PIONEER (NCT03731260) is an international, multicenter, randomized, double-blind, placebo-controlled, phase 2 study of avapritinib in patients with ISM and symptoms inadequately controlled by supportive care. Objectives included identifying the recommended phase 2 dose (RP2D) in part 1 (25 mg, 50 mg, 100 mg vs placebo), safety, and comparing the efficacy of avapritinib at RP2D versus placebo in part 2, based on change in total symptom score (TSS) assessed by the use of the ISM Symptom Assessment Form (scores ranging from 0 to 110). Changes in serum tryptase, marrow MC burden, and KIT D816V mutational burden were also measured. This abstract was presented previously at the 25^th European Hematology Association Congress, June 11-14, 2020, virtual format.

Results: Part 1 completed enrollment with 39 patients with ISM, treated with 25 mg once daily (n=10), 50 mg (n=10), or 100 mg avapritinib (n=10), or placebo (n=9) in 4-week cycles; 77% of patients were female, with median age (range) of 51 (21–75) years. As of December 27, 2019, 95% of patients remained on study with a median (range) of 18 (1–36) weeks. At baseline, 95% of patients were KIT D816V-positive in peripheral blood with median (range) variant allele fraction of 0.36% (0–30%) by central digital droplet PCR; median (range) bone marrow MC infiltrate was 10% (1–60%), serum tryptase was 45 ng/mL (6–416 ng/mL) and TSS was 52 (19–100). The most common adverse events (AEs) of any grade (placebo; avapritinib all doses) were nausea (22%; 37%), dizziness (22%; 33%), headache (11%; 30%), diarrhea (11%; 23%), and fatigue (11%; 20%). Grade 3 AEs occurred in 22% of placebo- and 20% of avapritinib-treated patients. None of the 10 patients treated at 25 mg had grade 3 AEs or dose modifications; of patients receiving 50 mg (n=10) and 100 mg (n=10), 20% and 40% had grade 3 AEs and 30% and 30% had dose modifications, respectively. A significant mean % reduction in TSS was observed at cycle 5 in avapritinib-treated patients (all cohorts combined) versus placebo (P=0.001). Improvements in all individual TSS symptoms assessed were observed at cycle 5 day 1 with 25 mg avapritinib. Across the avapritinib dose cohorts, mean reductions in symptoms were similar, and TSS trends observed in ongoing patients in the 25-mg dose group up to cycle 5 indicate that symptom burden reached similar levels to the 100-mg dose group over time. Based on tolerability and efficacy findings, 25 mg was selected as the RP2D for part 2. Analyzing the 25 mg avapritinib group in more detail, 7 of 10 patients exhibited a ≥50% reduction in serum tryptase, 7 of 10 patients cleared marrow MC aggregates and/or had a ≥50% reduction of marrow MCs, and 6 of 10 patients cleared or had a ≥50% reduction in blood KIT D816V allele fraction.

Conclusions: At the RP2D of 25 mg, avapritinib was well tolerated with no grade 3 AEs and no dose modifications. Marked patient-reported reductions from baseline in SM symptoms versus placebo were observed, associated with decreased levels of serum tryptase, bone marrow MC aggregates, and KIT D816V allele fraction in peripheral blood. Part 2 of PIONEER, which will assess the safety and efficacy of avapritinib RP2D of 25 mg once daily vs placebo, is open and enrolling with target enrollment of 204 patients.